Novel brain 14-3-3 interacting proteins involved in neurodegenerative disease.

We isolated two novel 14-3-3 binding proteins using 14-3-3 zeta as bait in a yeast two-hybrid screen of a human brain cDNA library. One of these encoded the C-terminus of a neural specific armadillo-repeat protein, delta-catenin (neural plakophilin-related arm-repeat protein or neurojungin). delta-Catenin from brain lysates was retained on a 14-3-3 affinity column. Mutation of serine 1072 in the human protein and serine 1094 in the equivalent site in the mouse homologue (in a consensus binding motif for 14-3-3) abolished 14-3-3 binding to delta-catenin in vitro and in transfected cells. delta-catenin binds to presenilin-1, encoded by the gene most commonly mutated in familial Alzheimer's disease. The other clone was identified as the insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53). Human IRSp53 interacts with the gene product implicated in dentatorubral-pallidoluysian atrophy, an autosomal recessive disorder associated with glutamine repeat expansion of atrophin-1.